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DNA sequence and chromatin modifiers cooperate to confer epigeneticbistability at imprinting control regions.
Butz S. et al.
Genomic imprinting is regulated by parental-specific DNA methylation of imprinting control regions (ICRs). Despite an identical DNA sequence, ICRs can exist in two distinct epigenetic states that are memorized throughout unlimited cell divisions and reset during germline formation. Here, we systematically study the ...

Smc5/6 silences episomal transcription by a three-step function.
Abdul F. et al.
In addition to its role in chromosome maintenance, the six-membered Smc5/6 complex functions as a restriction factor that binds to and transcriptionally silences viral and other episomal DNA. However, the underlying mechanism is unknown. Here, we show that transcriptional silencing by the human Smc5/6 complex is a t...

Exploration of nuclear body-enhanced sumoylation reveals that PMLrepresses 2-cell features of embryonic stem cells.
Tessier S. et al.
Membrane-less organelles are condensates formed by phase separation whose functions often remain enigmatic. Upon oxidative stress, PML scaffolds Nuclear Bodies (NBs) to regulate senescence or metabolic adaptation. PML NBs recruit many partner proteins, but the actual biochemical mechanism underlying their pleiotropi...

Loss of epigenetic regulation disrupts lineage integrity, inducesaberrant alveogenesis and promotes breast cancer.
Langille E. et al.
Systematically investigating the scores of genes mutated in cancer and discerning disease drivers from inconsequential bystanders is a prerequisite for Precision Medicine but remains challenging. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent 'long-tail' breast cancer genes, which...

RAD51 protects human cells from transcription-replication conflicts.
Bhowmick R. et al.
Oncogene activation during tumorigenesis promotes DNA replication stress (RS), which subsequently drives the formation of cancer-associated chromosomal rearrangements. Many episodes of physiological RS likely arise due to conflicts between the DNA replication and transcription machineries operating simultaneously at...

The Arabidopsis APOLO and human UPAT sequence-unrelated longnoncoding RNAs can modulate DNA and histone methylation machineries inplants.
Fonouni-Farde C. et al.
BACKGROUND: RNA-DNA hybrid (R-loop)-associated long noncoding RNAs (lncRNAs), including the Arabidopsis lncRNA AUXIN-REGULATED PROMOTER LOOP (APOLO), are emerging as important regulators of three-dimensional chromatin conformation and gene transcriptional activity. RESULTS: Here, we show that in addition to the PRC1...

Prolonged FOS activity disrupts a global myogenic transcriptionalprogram by altering 3D chromatin architecture in primary muscleprogenitor cells.
Barutcu A Rasim et al.
BACKGROUND: The AP-1 transcription factor, FBJ osteosarcoma oncogene (FOS), is induced in adult muscle satellite cells (SCs) within hours following muscle damage and is required for effective stem cell activation and muscle repair. However, why FOS is rapidly downregulated before SCs enter cell cycle as progenitor c...

Androgen-Induced MIG6 Regulates Phosphorylation ofRetinoblastoma Protein and AKT to Counteract Non-Genomic ARSignaling in Prostate Cancer Cells.
Schomann T. et al.
The bipolar androgen therapy (BAT) includes the treatment of prostate cancer (PCa) patients with supraphysiological androgen level (SAL). Interestingly, SAL induces cell senescence in PCa cell lines as well as ex vivo in tumor samples of patients. The SAL-mediated cell senescence was shown to be androgen receptor (A...

Variation in PU.1 binding and chromatin looping at neutrophil enhancersinfluences autoimmune disease susceptibility
Watt S. et al.
Neutrophils play fundamental roles in innate inflammatory response, shape adaptive immunity1, and have been identified as a potentially causal cell type underpinning genetic associations with immune system traits and diseases2,3 The majority of these variants are non-coding and the underlying mechanisms are not full...

CREBBP/EP300 acetyltransferase inhibition disrupts FOXA1-bound enhancers to inhibit the proliferation of ER+ breast cancer cells.
Bommi-Reddy A. et al.
Therapeutic targeting of the estrogen receptor (ER) is a clinically validated approach for estrogen receptor positive breast cancer (ER+ BC), but sustained response is limited by acquired resistance. Targeting the transcriptional coactivators required for estrogen receptor activity represents an alternative approach...

Transient regulation of focal adhesion via Tensin3 is required fornascent oligodendrocyte differentiation
Merour E. et al.
The differentiation of oligodendroglia from oligodendrocyte precursor cells (OPCs) to complex and extensive myelinating oligodendrocytes (OLs) is a multistep process that involves largescale morphological changes with significant strain on the cytoskeleton. While key chromatin and transcriptional regulators of diffe...

The long noncoding RNA H19 regulates tumor plasticity inneuroendocrine prostate cancer
Singh N. et al.
Neuroendocrine (NE) prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (PCa) arising either de novo or from transdifferentiated prostate adenocarcinoma following androgen deprivation therapy (ADT). Extensive computational analysis has identified a high degree of association between th...

Epromoters function as a hub to recruit key transcription factorsrequired for the inflammatory response
Santiago-Algarra D. et al.
Gene expression is controlled by the involvement of gene-proximal (promoters) and distal (enhancers) regulatory elements. Our previous results demonstrated that a subset of gene promoters, termed Epromoters, work as bona fide enhancers and regulate distal gene expression. Here, we hypothesized that Epromoters play a...

Differential contribution to gene expression prediction of histonemodifications at enhancers or promoters.
González-Ramírez M. et al.
The ChIP-seq signal of histone modifications at promoters is a good predictor of gene expression in different cellular contexts, but whether this is also true at enhancers is not clear. To address this issue, we develop quantitative models to characterize the relationship of gene expression with histone modification...

Atg7 deficiency in microglia drives an altered transcriptomic profileassociated with an impaired neuroinflammatory response
Friess L. et al.
Microglia, resident immunocompetent cells of the central nervous system, can display a range of reaction states and thereby exhibit distinct biological functions across development, adulthood and under disease conditions. Distinct gene expression profiles are reported to define each of these microglial reaction stat...

Lasp1 regulates adherens junction dynamics and fibroblast transformationin destructive arthritis
Beckmann D. et al.
The LIM and SH3 domain protein 1 (Lasp1) was originally cloned from metastatic breast cancer and characterised as an adaptor molecule associated with tumourigenesis and cancer cell invasion. However, the regulation of Lasp1 and its function in the aggressive transformation of cells is unclear. Here we use integrativ...

The lncRNA and the transcription factor WRKY42 target common cell wallEXTENSIN encoding genes to trigger root hair cell elongation.
Pacheco, J. M. et al.
Plant long noncoding RNAs (lncRNAs) are key chromatin dynamics regulators, directing the transcriptional programs driving a wide variety of developmental outputs. Recently, we uncovered how the lncRNA () directly recognizes the locus encoding the root hair (RH) master regulator () modulating its transcriptional acti...

Placental uptake and metabolism of 25(OH)Vitamin D determines itsactivity within the fetoplacental unit
Ashley, B. et al.
Pregnancy 25-hydroxyvitamin D (25(OH)D) concentrations are associated with maternal and fetal health outcomes, but the underlying mechanisms have not been elucidated. Using physiological human placental perfusion approaches and intact villous explants we demonstrate a role for the placenta in regulating the relation...

Waves of sumoylation support transcription dynamics during adipocytedifferentiation
Zhao, X. et al.
Tight control of gene expression networks required for adipose tissue formation and plasticity is essential for adaptation to energy needs and environmental cues. However, little is known about the mechanisms that orchestrate the dramatic transcriptional changes leading to adipocyte differentiation. We investigated ...

Androgen receptor positively regulates gonadotropin-releasing hormonereceptor in pituitary gonadotropes.
Ryan, Genevieve E. et al.
Within pituitary gonadotropes, the gonadotropin-releasing hormone receptor (GnRHR) receives hypothalamic input from GnRH neurons that is critical for reproduction. Previous studies have suggested that androgens may regulate GnRHR, although the mechanisms remain unknown. In this study, we demonstrated that androgens ...

Genetic perturbation of PU.1 binding and chromatin looping at neutrophilenhancers associates with autoimmune disease.
Watt, Stephen et al.
Neutrophils play fundamental roles in innate immune response, shape adaptive immunity, and are a potentially causal cell type underpinning genetic associations with immune system traits and diseases. Here, we profile the binding of myeloid master regulator PU.1 in primary neutrophils across nearly a hundred voluntee...

Fra-1 regulates its target genes via binding to remote enhancers withoutexerting major control on chromatin architecture in triple negative breastcancers.
Bejjani, Fabienne and Tolza, Claire and Boulanger, Mathias and Downes,Damien and Romero, Raphaël and Maqbool, Muhammad Ahmad and Zine ElAabidine, Amal and Andrau, Jean-Christophe and Lebre, Sophie and Brehelin,Laurent and Parrinello, Hughes and Rohmer,
The ubiquitous family of dimeric transcription factors AP-1 is made up of Fos and Jun family proteins. It has long been thought to operate principally at gene promoters and how it controls transcription is still ill-understood. The Fos family protein Fra-1 is overexpressed in triple negative breast cancers (TNBCs) w...

Cell-specific alterations inPitx1regulatory landscape activation caused bythe loss of a single enhancer
Rouco, R. et al.
Most developmental genes rely on multiple transcriptional enhancers for their accurate expression during embryogenesis. Because enhancers may have partially redundant activities, the loss of one of them often leads to a partial loss of gene expression and concurrent moderate phenotypic outcome, if any. While such a ...

Transgenic mice for in vivo epigenome editing with CRISPR-based systems
Gemberling, M. et al.
The discovery, characterization, and adaptation of the RNA-guided clustered regularly interspersed short palindromic repeat (CRISPR)-Cas9 system has greatly increased the ease with which genome and epigenome editing can be performed. Fusion of chromatin-modifying domains to the nuclease-deactivated form of Cas9 (dCa...

Transcriptional programming drives Ibrutinib-resistance evolution in mantlecell lymphoma.
Zhao, Xiaohong et al.
Ibrutinib, a bruton's tyrosine kinase (BTK) inhibitor, provokes robust clinical responses in aggressive mantle cell lymphoma (MCL), yet many patients relapse with lethal Ibrutinib-resistant (IR) disease. Here, using genomic, chemical proteomic, and drug screen profiling, we report that enhancer remodeling-mediated t...

Coordinated changes in gene expression, H1 variant distribution and genome3D conformation in response to H1 depletion
Serna-Pujol, Nuria and Salinas-Pena, Monica and Mugianesi, Francesca and LeDily, François and Marti-Renom, Marc A. and Jordan, Albert
Up to seven members of the histone H1 family may contribute to chromatin compaction and its regulation in human somatic cells. In breast cancer cells, knock-down of multiple H1 variants deregulates many genes, promotes the appearance of genome-wide accessibility sites and triggers an interferon response via activati...

REPROGRAMMING CBX8-PRC1 FUNCTION WITH A POSITIVE ALLOSTERICMODULATOR
Suh, J. L. et al.
Canonical targeting of Polycomb Repressive Complex 1 (PRC1) to repress developmental genes is mediated by cell type-specific, paralogous chromobox (CBX) proteins (CBX2, 4, 6, 7 and 8). Based on their central role in silencing and their misregulation associated with human disease including cancer, CBX proteins are at...

Germline activity of the heat shock factor HSF-1 programs theinsulin-receptor daf-2 in C. elegans
Das, S. et al.
The mechanisms by which maternal stress alters offspring phenotypes remain poorly understood. Here we report that the heat shock transcription factor HSF-1, activated in the C. elegans maternal germline upon stress, epigenetically programs the insulin-like receptor daf-2 by increasing repressive H3K9me2 levels throu...

The epigenetic landscape in purified myonuclei from fast and slow muscles
Bengtsen, M. et al.
Muscle cells have different phenotypes adapted to different usage and can be grossly divided into fast/glycolytic and slow/oxidative types. While most muscles contain a mixture of such fiber types, we aimed at providing a genome-wide analysis of chromatin environment by ChIP-Seq in two muscle extremes, the almost co...

The glucocorticoid receptor recruits the COMPASS complex to regulateinflammatory transcription at macrophage enhancers.
Greulich, Franziska et al.
Glucocorticoids (GCs) are effective anti-inflammatory drugs; yet, their mechanisms of action are poorly understood. GCs bind to the glucocorticoid receptor (GR), a ligand-gated transcription factor controlling gene expression in numerous cell types. Here, we characterize GR's protein interactome and find the SETD1A ...

A distinct metabolic response characterizes sensitivity to EZH2inhibition in multiple myeloma.
Nylund P. et al.
Multiple myeloma (MM) is a heterogeneous haematological disease that remains clinically challenging. Increased activity of the epigenetic silencer EZH2 is a common feature in patients with poor prognosis. Previous findings have demonstrated that metabolic profiles can be sensitive markers for response to treatment i...

BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma
Laubscher et. al.
Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage. The aggressive alveolar subtype is characterized by t(2;13) or t(1;13) translocations encoding for PAX3- or PAX7-FOXO1 chimeric transcription factors, respectively, and are referred to as fusion positive RMS (FP-RMS). The fusion gene alters...

A Tumor Suppressor Enhancer of PTEN in T-cell development and leukemia
L. Tottone at al.
Long-range oncogenic enhancers play an important role in cancer. Yet, whether similar regulation of tumor suppressor genes is relevant remains unclear. Loss of expression of PTEN is associated with the pathogenesis of various cancers, including T-cell leukemia (T-ALL). Here, we identify a highly conserved distal enh...

Stronger induction of trained immunity by mucosal BCG or MTBVAC vaccination compared to standard intradermal vaccination.
Vierboom, M.P.M. et al.
BCG vaccination can strengthen protection against pathogens through the induction of epigenetic and metabolic reprogramming of innate immune cells, a process called trained immunity. We and others recently demonstrated that mucosal or intravenous BCG better protects rhesus macaques from infection and TB disease than...

Postoperative abdominal sepsis induces selective and persistent changes inCTCF binding within the MHC-II region of human monocytes.
Siegler B. et al.
BACKGROUND: Postoperative abdominal infections belong to the most common triggers of sepsis and septic shock in intensive care units worldwide. While monocytes play a central role in mediating the initial host response to infections, sepsis-induced immune dysregulation is characterized by a defective antigen present...

S-adenosyl-l-homocysteine hydrolase links methionine metabolism to thecircadian clock and chromatin remodeling.
Greco C. M. et al.
Circadian gene expression driven by transcription activators CLOCK and BMAL1 is intimately associated with dynamic chromatin remodeling. However, how cellular metabolism directs circadian chromatin remodeling is virtually unexplored. We report that the S-adenosylhomocysteine (SAH) hydrolyzing enzyme adenosylhomocyst...

Genomic profiling of T-cell activation suggests increased sensitivity ofmemory T cells to CD28 costimulation.
Glinos, Dafni A and Soskic, Blagoje and Williams, Cayman and Kennedy, Alanand Jostins, Luke and Sansom, David M and Trynka, Gosia
T-cell activation is a critical driver of immune responses. The CD28 costimulation is an essential regulator of CD4 T-cell responses, however, its relative importance in naive and memory T cells is not fully understood. Using different model systems, we observe that human memory T cells are more sensitive to CD28 co...

A genetic variant controls interferon-β gene expression in human myeloidcells by preventing C/EBP-β binding on a conserved enhancer.
Assouvie, Anaïs and Rotival, Maxime and Hamroune, Juliette and Busso,Didier and Romeo, Paul-Henri and Quintana-Murci, Lluis and Rousselet,Germain
Interferon β (IFN-β) is a cytokine that induces a global antiviral proteome, and regulates the adaptive immune response to infections and tumors. Its effects strongly depend on its level and timing of expression. Therefore, the transcription of its coding gene IFNB1 is strictly controlled. We have previous...

BCG Vaccination Induces Long-Term Functional Reprogramming of HumanNeutrophils.
Moorlag, Simone J C F M and Rodriguez-Rosales, Yessica Alina and Gillard,Joshua and Fanucchi, Stephanie and Theunissen, Kate and Novakovic, Borisand de Bont, Cynthia M and Negishi, Yutaka and Fok, Ezio T and Kalafati,Lydia and Verginis, Panayotis and M
The tuberculosis vaccine bacillus Calmette-Guérin (BCG) protects against some heterologous infections, probably via induction of non-specific innate immune memory in monocytes and natural killer (NK) cells, a process known as trained immunity. Recent studies have revealed that the induction of trained immunit...

Macrophage Immune Memory Controls Endometriosis in Mice and Humans.
Jeljeli, Mohamed and Riccio, Luiza G C and Chouzenoux, Sandrine and Moresi,Fabiana and Toullec, Laurie and Doridot, Ludivine and Nicco, Carole andBourdon, Mathilde and Marcellin, Louis and Santulli, Pietro and Abrão,Mauricio S and Chapron, Charles and
Endometriosis is a frequent, chronic, inflammatory gynecological disease characterized by the presence of ectopic endometrial tissue causing pain and infertility. Macrophages have a central role in lesion establishment and maintenance by driving chronic inflammation and tissue remodeling. Macrophages can be reprogra...

UTX/KDM6A suppresses AP-1 and a gliogenesis program during neuraldifferentiation of human pluripotent stem cells.
Xu, Beisi and Mulvey, Brett and Salie, Muneeb and Yang, Xiaoyang andMatsui, Yurika and Nityanandam, Anjana and Fan, Yiping and Peng, Jamy C
BACKGROUND: UTX/KDM6A is known to interact and influence multiple different chromatin modifiers to promote an open chromatin environment to facilitate gene activation, but its molecular activities in developmental gene regulation remain unclear. RESULTS: We report that in human neural stem cells, UTX binding correla...

Epigenetic regulation of the lineage specificity of primary human dermallymphatic and blood vascular endothelial cells.
Tacconi, Carlotta and He, Yuliang and Ducoli, Luca and Detmar, Michael
Lymphatic and blood vascular endothelial cells (ECs) share several molecular and developmental features. However, these two cell types possess distinct phenotypic signatures, reflecting their different biological functions. Despite significant advances in elucidating how the specification of lymphatic and blood vasc...

Combined treatment with CBP and BET inhibitors reverses inadvertentactivation of detrimental super enhancer programs in DIPG cells.
Wiese, M and Hamdan, FH and Kubiak, K and Diederichs, C and Gielen, GHand Nussbaumer, G and Carcaboso, AM and Hulleman, E and Johnsen, SA andKramm, CM
Diffuse intrinsic pontine gliomas (DIPG) are the most aggressive brain tumors in children with 5-year survival rates of only 2%. About 85% of all DIPG are characterized by a lysine-to-methionine substitution in histone 3, which leads to global H3K27 hypomethylation accompanied by H3K27 hyperacetylation. Hyperacetyla...

Methylation in pericytes after acute injury promotes chronic kidneydisease.
Chou, YH and Pan, SY and Shao, YH and Shih, HM and Wei, SY andLai, CF and Chiang, WC and Schrimpf, C and Yang, KC and Lai, LC andChen, YM and Chu, TS and Lin, SL
The origin and fate of renal myofibroblasts is not clear after acute kidney injury (AKI). Here, we demonstrate that myofibroblasts were activated from quiescent pericytes (qPericytes) and the cell numbers increased after ischemia/reperfusion injury-induced AKI (IRI-AKI). Myofibroblasts underwent apoptosis during ren...

Exploring the virulence gene interactome with CRISPR/dCas9 in the humanmalaria parasite.
Bryant, JM and Baumgarten, S and Dingli, F and Loew, D and Sinha, A andClaës, A and Preiser, PR and Dedon, PC and Scherf, A
Mutually exclusive expression of the var multigene family is key to immune evasion and pathogenesis in Plasmodium falciparum, but few factors have been shown to play a direct role. We adapted a CRISPR-based proteomics approach to identify novel factors associated with var genes in their natural chromatin context. Ca...

Targeted bisulfite sequencing for biomarker discovery.
Morselli, M and Farrell, C and Rubbi, L and Fehling, HL and Henkhaus, Rand Pellegrini, M
Cytosine methylation is one of the best studied epigenetic modifications. In mammals, DNA methylation patterns vary among cells and is mainly found in the CpG context. DNA methylation is involved in important processes during development and differentiation and its dysregulation can lead to or is associated with dis...

Battle of the sex chromosomes: competition between X- and Y-chromosomeencoded proteins for partner interaction and chromatin occupancy drivesmulti-copy gene expression and evolution in muroid rodents.
Moretti, C and Blanco, M and Ialy-Radio, C and Serrentino, ME and Gobé,C and Friedman, R and Battail, C and Leduc, M and Ward, MA and Vaiman, Dand Tores, F and Cocquet, J
Transmission distorters (TDs) are genetic elements that favor their own transmission to the detriments of others. Slx/Slxl1 (Sycp3-like-X-linked and Slx-like1) and Sly (Sycp3-like-Y-linked) are TDs which have been co-amplified on the X and Y chromosomes of Mus species. They are involved in an intragenomic conflict i...

BET protein inhibition sensitizes glioblastoma cells to temozolomidetreatment by attenuating MGMT expression
Tancredi A. et al.
Bromodomain and extra-terminal tail (BET) proteins have been identified as potential epigenetic targets in cancer, including glioblastoma. These epigenetic modifiers link the histone code to gene transcription that can be disrupted with small molecule BET inhibitors (BETi). With the aim of developing rational combin...